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Author
Topic: Summary of what might be on the treatment horizon... (Read 4699 times)

This is good summary from the March 2006 Hopkins HIV Report about treatment developments. The ... are deleted segments to shorten the article.

4 + 5 = 9: New Drug Targets Add UpBy Charles Flexner, M.D.

Today there are only four classes of approved antiretroviral drugs: the nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitor s (NNRTIs), protease inhibitors (PI)s, and one fusion inhibitor, enfuvirtide. These agents attack four different targets on three different HIV proteins. Identification of drugs that block other steps in the HIV life cycle is a major goal of new drug development. In part, this is based on the assumption that drugs attacking new targets will not be cross-resistant with those in existing classes.

The 13th CROI in Denver provided promising clinical results for several new classes of antiretroviral drugs. Drugs aimed at five new targets were reported to have anti-HIV activity in patients (including the CXCR4 antagonists not discussed here). If all of these agents continue to show promise and advance to approval by the FDA, there will be a minimum of nine different classes of antiretroviral agents. In a few years, choices for providers and patients are likely to be more numerous, and options for treatment-experienced patients will grow.

The Integrase Race Takes Off

Integrase is an HIV enzyme that catalyzes a strand transfer reaction essential for the integration of proviral DNA into the host chromosome. At the 12th CROI we learned that the first integrase inhibitor tested in HIV-infected patients showed substantial antiviral activity, reducing plasma viral load by more than two log10…The bad news is that one inhibitor, Merck’s L000870810, had to be pulled from further development because of animal toxicity, even though it was well tolerated in patients.

Fortunately Merck had a back-up compound, MK-0518, that has moved very quickly into human trials. A study in treatment-naïve patients was presented at the European AIDS Clinical Society meeting in Dublin last November, and reported a 1.7-2.2 log10 drop in viral load after 10 days of monotherapy, similar to results seen with L-000870810…A new study presented in Denver evaluated MK-0518 added to an optimized background regimen (OBR) in 167 heavily treatment-experienced patients…After 8 weeks of treatment, 63-67% of MK-0518 treated patients had a viral load <50 c/mL, compared to only 8% of patients treated with OBR plus placebo. Similar results were reported at Week 16, but only about half of subjects had reached this time point at the time of the presentation…This is an impressive result given the highly drug resistant patient population studied. MK-0518 has shown no significant drug-related toxicities in clinical trials to date…

Early success with L-000870810 encouraged several of Merck’s competitors to pursue integrase inhibitors of their own. One of these drugs, GS-9137/JTK-303, which was discovered by Japanese Tobacco but is being developed clinically by Gilead, was reported to have antiretroviral activity in another late breaking abstract…Fifteen treatment-naïve and 15 treatment-experienced patients were randomly assigned to 10 days of GS-9137 monotherapy…Compared to 10 subjects who received placebo, all GS-9137 regimens produced a median reduction in viral load that ranged from 0.96 to 2.03 log10…GS-9137 is chemically distinct from MK-0518, and would therefore be predicted to have little or no cross-resistance with the other integrase inhibitor…The drug must be given with food and is reported to be a moderate P450 inducer but not an inhibitor. There were no significant drug related toxicities in this short-term trial. This initial study suggests that the drug could be administered as a twice daily agent without ritonavir or as a once daily agent with ritonavir.

Vicriviroc: Another Set-back for CCR5 Inhibitors

Last year was not good for the new CCR5 chemokine receptor antagonists. Aplaviroc, the GSK CCR5 antagonist, was pulled from development in early 2005 because of unexpected severe liver toxicity…Another case of liver toxicity requiring transplantation was reported with maraviroc, the Pfizer compound, but that case was attributed to other causes and the drug continues in Phase 3 clinical trials. In October, 2005, the first Phase 2 trial of the Schering CCR5 antagonist, vicriviroc, was stopped because of low rates of virologic suppression compared to the control arm, efavirenz (EFV) plus zidovudine/lamivudine (AZT/3TC, Combivir)… It appears that the selected doses of vicriviroc may have been too low, allowing room for exploration of higher doses in future studies…A Phase 2 study of this drug at lower doses but in combination with ritonavir in treatment experienced patients is continuing through the AIDS Clinical Trials Group, and is expected to be ready for analysis in late 2006…

PA-457: Update on a New Maturation Inhibitor

Another drug whose dose might still be too low is PA-457. This drug is the first in a new class of molecules called maturation inhibitors. These agents have the same effect on the virus as protease inhibitors, by blocking the processing of the gag precursor polyprotein that must be cleaved in order for the virus to become infectious. But unlike PIs, PA-457 achieves this by binding directly to the gag polyprotein; it does not bind to the protease…investigators from the University at Buffalo, NY (formerly SUNY Buffalo)…suggested that doses higher than the 200 mg qd maximum might produce viral load reductions greater than the mean 1.1 log10 decline reported, and could produce monotherapy effects as great as that seen with the PIs and NNRTIs. Unfortunately, some PA-457 recipients even at the highest doses showed little change in viral load, and an explanation for that observation is lacking. Although resistance to PA-457 occurs in vitro…, no resistance has been detected in patients, even those who failed to respond to the drug in monotherapy studies…The authors of the resistance study suggest that the PA-457 binding site is highly conserved, and resistance may occur with a substantial cost in terms of viral fitness.

TNX-355: An Anti-CD4 Monoclonal Antibody

TNX-355 is a humanized monoclonal antibody that binds to a part of the CD4 receptor that is essential for HIV entry. This antibody does not block the HIV outer envelope protein gp120 from binding to CD4; rather, it interferes with a conformational change in CD4 that is essential for access of gp120 to the chemokine receptors CCR5 or CXCR4. The antibody is equally active against CCR5- and CXCR4-trophic virus isolates. The antiretroviral activity of this agent in patients was first reported in 2003…Highly treatment experienced patients who receive an injection of TNX-355 every 2 weeks have a sustained average drop in viral load of about 1.0 log10 after 24 weeks. There has been hope that resistance would not develop with this agent, since it targets the host rather than a virus-encoded protein. However, some treated patients show little virologic benefit, suggesting the possibility of resistance.

Investigators from Tanox examined the TNX-355 sensitivity of baseline HIV isolates from 82 patients participating in an ongoing Phase 2 treatment trial…They reported that TNX-355-resistant strains have modifications in their envelope proteins that result in altered envelope conformation. The gp120 trimers that normally form in the process of HIV entry are more open in these strains, allowing access to coreceptors even in the presence of the antibody…This remains an intriguing approach to therapy, whose main role would probably be in salvage. Although the compound is likely to be expensive and must be given by injection every two weeks, it is likely to have some advantages in cost and convenience over enfuvirtide. A big question is whether the resistance reported at CROI will become more widespread.

What’s Next for Entry Inhibitors?

Enfuvirtide (ENF, T-20) is the only entry inhibitor approved for the treatment of HIV infection. This peptide has the drawbacks of high cost and the requirement for twice-daily injection, often resulting in painful subcutaneous nodules. A second generation entry inhibitor, T-1249, had better pharmacokinetic properties and could be given once daily, but was pulled from development in part for economic reasons. Although several oral entry inhibitors have been evaluated, none has made it past Phase 2.

Investigators from Trimeris reported the development of a third generation of ENF peptide analogs, designed for better antiviral potency and improved pharmacokinetics…One of these analogs, T-290999, is about 10-fold more potent in vitro against ENF sensitive virus and >100-fold more potent against ENF-resistant virus than ENF. “T-999” and another analog called TR-291144 are modified by adding a fatty acid to a traditional ENF-like peptide. This not only appears to improve anti-HIV activity, but also to greatly slow elimination from the body after injection. In pharmacokinetic studies conducted in monkeys, both drugs had much longer half-lives than ENF, and sustained concentrations higher than the IC50 for HIV for more than a week after injection…A new generation of entry inhibitors that could be injected once a week, or even less frequently, would be a major advance in HIV therapy…

Merck has released their DNA genetic vaccine. Although there is no immunity from this vaccine, the vaccine does produce as much as 2,000 neutralizing antibodies. One of my concerns was that Merck is using the Adenovirus Vector and data seems to indicate that a good percentage of the population won't respond to this vector because it is so commonly found in nature generally.

A German Researcher recently came up with a way of modifying the Adenovirus Vector and found that the modification did cause the bodies immune system to recognize the Adenovirus Vector as a foreign substance. My question is whether or not Merck is incorporating this new vector into their treatment strategy. Someone needs to contact Merck to find out what the status is?